A. Louilot

Opposite influences of dopaminergic pathways to the prefrontal cortex or the septum on the dopaminergic transmission in the nucleus accumbens. An in vivo voltammetric study.

Modulation of dopaminergic transmission in the nucleus accumbens by the dopaminergic pathways reaching the prefrontal cortex (anteromedian and the suprarhinal parts) and the lateral septum was investigated. Changes in dopaminergic transmission in the nucleus accumbens were assessed by in vivo voltammetry using pretreated carbon fiber electrodes. This technique allows the selective detection of 3,4-dihydroxyphenylacetic acid, the main presynaptic metabolite of dopamine. Dopaminergic transmission in the prefrontal cortex (anteromedian and suprarhinal parts) and the lateral septum was altered by local injection of the dopaminergic agonist (d-amphetamine) and the dopaminergic antagonists (alpha-flupenthixol and sulpiride). Pharmacological interventions, either stimulation or blockade, in the anteromedian and suprarhinal parts of the prefrontal cortex induced, respectively, a decrease or an increase in extracellular 3,4-dihydroxyphenylacetic acid in the nucleus accumbens. The same pharmacological interventions in the lateral septum had exactly opposite effects in the nucleus accumbens. The inhibitory action of the mesocortical and mesorhinal dopaminergic projections and the facilitatory action of the mesoseptal dopaminergic projection on dopaminergic input in the nucleus accumbens were shown to rely on the activity of inhibitory fugal pathways which could be blocked by local injection of tetrodotoxin in the three structures. In a previous work, it was demonstrated that dopaminergic projections in the amygdala exert an inhibitory influence on dopaminergic transmission in the nucleus accumbens. Thus the present results suggest that functional interdependence between the different dopaminergic pathway arising in the ventral mesencephalon is a general property of this neuronal group. Data obtained after manipulation of dopaminergic transmission in these various projection areas may need to be interpret in a different light. Similarly, neurological and psychiatric observations may need to be reconsidered in view of the interdependence of the dopaminergic mesencephalic pathways.

Modulation of dopaminergic activity in the nucleus accumbens following facilitation or blockade of the dopaminergic transmission in the amygdala: a study by in vivo differential pulse voltammetry

Using in vivo voltammetry, dopaminergic (DAergic) activity in the nucleus accumbens (ACC) was assessed following microinjection of DAergic agonists and antagonists in the amygdala (AMY). It was found that DAergic activity in the ACC was under the inhibitory influence of DAergic transmission in the AMY. Therefore, it can be suggested that there is a functional interdependence between the activity of these two DAergic pathways originating from the ventral mesencephalic region.

Alternation behavior, spatial discrimination, and reversal disturbances following 6-hydroxydopamine lesions in the nucleus accumbens of the rat

The effects of dopaminergic depletion of the nucleus accumbens was tested in various behavioral tasks such as alternation, spatial discrimination, and reversal learning, and in an extinction paradigm in a T maze. Animals with lesions showed impairment of spontaneous alternation behavior, disturbances in the acquisition of spatial discrimination, and great difficulty in reversing previously learned habits. In the extinction phase, experimental animals are unable to adjust their behavior, and continue to choose the previously reinforced arm of the T maze. It is suggested that the nucleus accumbens plays an important role in the transition of motivation into action, and that dopamine has a facilitatory influence on the mediation of these processes.

Behavioral study after local injection of 6-hydroxydopamine into the nucleus accumbens in the rat

Anatomically, the nucleus accumbens (n.Acc.) has been considered as an interface between limbic and striatal sensorimotor structures. In the light of this hypothesis we have investigated the behavioral effects of destruction of the dopaminergic innervation of the n.Acc. after local injection of 6-hydroxydopamine. The following behavioral deficits were observed: hypoexploration in a 4-hole box and 2-compartment field, failure to inhibit response strategies either with positive reinforcement in a straight alley test or negative reinforcement in a passive avoidance test. These disturbances comprise a syndrome of perseveration, reduced distraction by irrelevant information, decreased behavioral switching and flexibility, and a paradoxical locomotor disinhibition in an emotional context. Very similar behavioral changes are found following lesions of limbic structures. In addition, these lesioned animals exhibit an enhanced latency to initiate motor responses. This deficit of behavioral initiation is classically observed in motor striatal disease. It is suggested that the n.Acc. is a key structure for the integration of limbic and striatal sensorimotor functions.

Lateralized interdependence between limbicotemporal and ventrostriatal dopaminergic transmission

The antipsychotic effects of dopaminergic antagonists suggest dopaminergic hyperactivity plays a role in schizophrenia. However, an elevated number of D2 dopamine receptors in the left putamen of non-treated schizophrenics has been reported which is consistent with a diminution of dopaminergic transmission in the ventral striatum. Morphological and functional studies have shown marked alterations in the left medial temporal lobe (entorhinal cortex, hippocampus, parahippocampus gyrus) of schizophrenics. As the entorhinal cortex and the ventral hippocampus project to the ventral striatum, the functional relationship between left temporal structures and the left ventral striatum may be impaired in schizophrenics. To assess the validity of this hypothesis, we investigated the existence of a preferentially left hemispheric interdependency between dopaminergic pathways in male rats. We found that dopaminergic projections in the entorhinal cortex and the ventral hippocampus regulate dopaminergic transmission in the nucleus accumbens, particularly in the left hemisphere. Temporal D2 dopamine receptors seem to be primarily involved in this effect. This lateralized interdependent functioning appears structurally based. These results may provide new insights into the pathophysiology of schizophrenic psychoses.

Dissociation in the involvement of dopaminergic neurons innervating the core and shell subregions of the nucleus accumbens in latent inhibition and affective perception

Mesencephalic dopaminergic neurons have been found to be involved in affective processes. Their implication in cognitive processes appears less well understood. The use of latent inhibition paradigms is a means of studying these kinds of processes. In this study, we investigated the involvement of dopaminergic projections in the core, the dorsomedial shell and the ventromedial shell of the nucleus accumbens, in latent inhibition in olfactory aversive learning. Variations in extracellular dopamine levels induced by an aversively conditioned olfactory stimulus were monitored in the three parts of the nucleus accumbens in the left hemisphere, after pre-exposure to the olfactory stimulus using in vivo voltammetry in freely moving rats. The parallel between dopamine changes and place preference or aversion toward the stimulus were analyzed in pre-exposed and non-pre-exposed animals. Results showed that dopaminergic neurons innervating the nucleus accumbens are differentially involved in the latent inhibition phenomenon. Dopaminergic neurons innervating the core and the dorsomedial shell subregions of the nucleus accumbens appeared to be involved in latent inhibition processes, unlike those reaching the ventromedial shell. Nonetheless dopamine in the ventromedial shell was found to be involved in affective perception of the stimulus.The present data suggest that dopaminergic neurons innervating the three nucleus accumbens subregions are functionally related to networks involved in parallel processing of the cognitive and affective values of environmental information, and that interaction between these systems, at some levels, may lead to a given behavioral output. These data may provide new insights into the pathophysiology of schizophrenic psychoses.

Effects of d- and l-amphetamine on dopamine metabolism and ascorbic acid levels in nucleus accumbens and olfactory tubercle as studied by in vivo differential pulse voltammetry

Differential pulse voltammetry used together with electrochemically pretreated carbon fibre microelectrodes allowed us to detect in vivo two well-separated peaks in nucleus accumbens and olfactory tubercle. The two peaks situated at -50 mV (peak 1) and + 100 mV (peak 2) correspond, respectively, to the oxidation current of the ascorbic acid and to the oxidation current of the 3,4-dihydroxyphenylacetic acid (DOPAC). The experiments were carried out on anesthetized rats. Voltammograms were recorded in nucleus accumbens and olfactory tubercle every minute alternately in each structure. In control conditions, peak 1 height was greater in olfactory tubercle than in nucleus accumbens and peak 2 height was greater in nucleus accumbens than in olfactory tubercle. Both isomers of amphetamine induced a decrease of the peak 2 height in the two structures. The decrease was greater in olfactory tubercle. Higher doses of L-amphetamine were required to induce peak 2 height decrease of the same extent. Both isomers induced a marked increase of the peak 1 height in nucleus accumbens whereas peak 1 height in olfactory tubercle was slightly augmented. D-amphetamine was more effective than L-amphetamine in increasing peak 1 height.

Effect of haloperidol and sulpiride on dopamine metabolism in nucleus accumbens and olfactory tubercle: A study by in vivo voltammetry

Differential pulse voltammetry used with electrochemically pretreated carbon fibre microelectrodes enables separation between the two peaks corresponding to the ascorbic acid and catechol oxidation currents. The effects of haloperidol and sulpiride on the 3,4-dihydroxyphenylacetic acid peak recorded in the nucleus accumbens and olfactory tubercle of rats were studied. Chloral hydrate anaesthetized preparations and chronic preparations were used. A microdevice was designed to implant electrodes in freely moving rats. Voltammograms were recorded every minute in each structure in acute preparations and every 2 min in chronic preparations. In acute preparations haloperidol induced a similar dose-dependent increase in the catechol oxidation peak in both structures. Sulpiride at all doses only induced an increase in the olfactory tubercle. In chronic preparations haloperidol and sulpiride had even larger effects on the 3,4-dihydroxyphenylacetic acid peak in both regions. In these preparations sulpiride induced a significant increase in nucleus accumbens. The effects induced by haloperidol in the two regions were greater than those induced by sulpiride. The main conclusions of this study are that the results of voltammetry agree with biochemical results on the effects of haloperidol and sulpiride on dopamine metabolism. An interaction of chloral hydrate with the effects of the two neuroleptics was also observed.

Asymmetrical increases in dopamine turn-over in the nucleus accumbens and lack of changes in locomotor responses following unilateral dopaminergic depletions in the entorhinal cortex

Functional interdependence between mesencephalic dopaminergic pathways is an emerging concept. Using in vivo voltammetry and acute manipulation of dopaminergic transmission with pharmacological agents, we have previously reported the existence of a preferentially left lateralized functional interdependence between the entorhinal cortex and the nucleus accumbens. The aim of the present work was to test if this phenomenon is only a dynamic process or if compensation occurs when interdependent functioning is considered in a more long-term perspective. In this study 6-OHDA lesions of the dopamine terminals of the entorhinal cortex were performed separately in the left and right hemispheres. Spontaneous and (+)-amphetamine stimulated locomotor activity were recorded 3 weeks after unilateral interventions in the Ent. Variations in DA and DOPAC levels were measured in the nucleus accumbens 5 weeks after the lesion. The following results were obtained. After unilateral 6-OHDA in the left Ent, DA and DOPAC tissue contents as well as the DOPAC/DA ratio were found significantly changed in nucleus accumbens in the two hemispheres. After dopaminergic destruction in the right Ent only the DOPAC/DA ratio in the left Acc was found statistically elevated. No differences in spontaneous or (+)-amphetamine-stimulated locomotor activity were observed after either left or right lesions. These data confirm those previously obtained with the voltammetric approach and further support the existence of an asymmetrical functional interdependence between mesencephalic DAergic pathways reaching the Ent and the Acc. These results may provide new insights in the pathophysiology of schizophrenic psychoses.

DIFFERENTIAL INVOLVEMENT OF DOPAMINE IN THE ANTERIOR AND POSTERIOR PARTS OF THE DORSAL STRIATUM IN LATENT INHIBITION

The involvement of mesostriatal dopaminergic neurons in cognitive operations is not well understood, and needs to be further clarified. The use of latent inhibition paradigms is a means of investigating cognitive processes. In this study, we investigated the involvement in latent inhibition of dopaminergic inputs in the anterior part and posterior part of the dorsal striatum. The latent inhibition phenomenon was observed in a conditioned olfactory aversion paradigm. Changes in extracellular dopamine levels induced by the conditioned olfactory stimulus (banana odor) were monitored in the two parts of the dorsal striatum in the left hemisphere after pre-exposure to the olfactory stimulus using in vivo voltammetry in freely moving rats. During the conditioning session animals received either an i.p. injection of NaCl (0.9%) (control groups) or an i.p. injection of LiCl (0.15 M) (conditioned groups). Dopamine variations and place preference or aversion toward the stimulus were analyzed simultaneously in pre-exposed and non-pre-exposed animals. Data collected during the retention (test) session were as follows. Where the anterior part of the striatum was concerned, similar enhancements in dopamine levels (+100%) were obtained in pre-exposed and non-pre-exposed control animals, as well as in the pre-exposed experimental animals. In contrast, dopamine levels in the non-pre-exposed experimental group (conditioned animals) remained fairly consistently close to the baseline after the presentation of the olfactory stimulus. Where the posterior part of the striatum was concerned, increases in extracellular dopamine levels were similar (+50%) for the different groups. The present results suggested that dopaminergic neurons reaching the anterior part of the dorsal striatum are implicated in the latent inhibition phenomenon and affective perception, whereas dopaminergic terminals in the posterior part of the dorsal striatum appeared to be involved neither in latent inhibition nor in affective perception of the stimulus, seeming only to be affected by the intrinsic properties of the stimulus. Cognitive as well as affective deficits have been reported in patients with schizophrenia. Thus the present data may be considered in the context of the pathophysiology of schizophrenic psychoses.